Epstein-Barr Virus (EBV) is a world-wide pathogen of man and over 80% of all adults are latently infected by the virus. Historically, two malignant diseases, African Burkitts lymphoma and nasopharyngeal carcinoma, have been closely associated with latent infections by EBV. However, no evidence precludes roles for chronic or reactivated EBV lytic infections in the development of these malignancies. Indeed, EBV-associated B-cell lymphomas develop with an increased incidence in immunologically comprised individuals such as those with genetic X-linked immunology, those undergoing organ transplants, and AIDS patients after primary or reactivated infections. An increased incidence of central nervous system lymphoma and the occurrence of hairy leukoplakia of the tongue also appear to be EBV-associated in AIDS patients. Thus, the conditions that result in failure of the host's immunological surveillance would also lead to chronic or reactivated lytic EBV replication and some of the viral or cellular factors involved in the lytic replicative processes of EBV may have an indirect role in the development of EBV-associated malignancies, as well as direct role in post-adolescent infectious mononucleosis. The overall goal of the proposed research is to understand the mechanisms involved in the induction and control of lytic EBV infection. The Specific Aims include: (1) isolation and characterization of the cellular and viral proteins that interact with sequence elements within orilyt that control DNA replication; and (2) identification and characterization of the EBV genes and their products that are essential for DNA replication beginning at orilyt; (3) identification and isolation of the intracellular signals leading to the expression of lytic viral genes and to DNA replication beginning at the lytic origin (orilyt) of the EBV genome.